Energy landscapes of Aβ monomers are sculpted in accordance with Ostwald's rule of stages.

ABSTRACT: The transition from a disordered to an assembly-competent monomeric state (N*) in amyloidogenic sequences is a crucial event in the aggregation cascade. Using a well-calibrated model for intrinsically disordered proteins (IDPs), we show that the N* states, which bear considerable resemblance to the polymorphic fibril structures found in experiments, not only appear as excitations in the free energy landscapes of Aβ40 and Aβ42, but also initiate the aggregation cascade. For Aβ42, the transitions to the different N* states are in accord with Ostwald's rule of stages, with the least stable structures forming ahead of thermodynamically favored ones. The Aβ40 and Aβ42 monomer landscapes exhibit different extents of local frustration, which we show have profound implications in dictating subsequ

SUBMITTER: Chakraborty D 

PROVIDER: S-EPMC10032606 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature